Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, Guizhou 550014, P.R. China.
Int J Oncol. 2017 Aug;51(2):456-466. doi: 10.3892/ijo.2017.4027. Epub 2017 Jun 2.
The ETS transcription factors play a critical role during hematopoiesis. In F-MuLV-induced erythroleukemia, Fli‑1 insertional activation producing high expression of this transcription factor required to promote proliferation. How deregulated Fli‑1 expression alters the balance between erythroid differentiation and proliferation is unknown. To address this issue, we exogenously overexpressed Fli‑1 in an erythroleukemic cell harboring activation of spi‑1/PU.1, another ETS gene involved in erythroleukemogenesis. While the proliferation in culture remains unaffected, Fli‑1 overexpression imparts morphological and immunohistochemical characteristics of immature erythroid progenitors. Fli‑1 overexpression in erythroleukemic cells increased the numbers of erythroid colonies on methylcellulose and reduced tumorigenicity as evidenced by increase latency of erythroleukemogenesis in mice inoculated with these cells. Although all transplanted mice developed enlargement of the spleen and liver due to leukemic infiltration, Fli‑1 overexpression altered the hematopoietic phenotype, significantly increasing the expression of regulatory hematopoietic genes cKIT, SCA-1, CD41 and CD71. In contrast, expression of Spi‑1/PU.1 in a Fli‑1 producing erythroleukemia cell line in which fli‑1 is activated, resulted in increased proliferation through activation of growth promoting proteins MAPK, AKT, cMYC and JAK2. Importantly, these progenitors express high levels of markers such as CD71 and TER119 associated with more mature erythroid cells. Thus, Fli‑1 overexpression induces a de-differentiation program by reverting CFU-E to BFU-E erythroid progenitor activity, while Spi‑1/PU.1 promoting maturation from BFU-E to CFU-E.
ETS 转录因子在造血过程中起着关键作用。在 F-MuLV 诱导的红细胞白血病中，Fli-1 插入激活导致这种转录因子的高表达，这是促进增殖所必需的。Fli-1 表达失调如何改变红细胞分化和增殖之间的平衡尚不清楚。为了解决这个问题，我们在一个含有 spi-1/PU.1 激活的红细胞白血病细胞中过表达 Fli-1，spi-1/PU.1 是另一个参与红细胞白血病发生的 ETS 基因。虽然培养中的增殖不受影响，但 Fli-1 的过表达赋予了不成熟红细胞祖细胞的形态和免疫组织化学特征。在红细胞白血病细胞中过表达 Fli-1 增加了甲基纤维素上的红细胞集落数量，并降低了肿瘤发生能力，这表现在用这些细胞接种的小鼠中红细胞白血病发生的潜伏期增加。虽然所有移植的小鼠由于白血病浸润而导致脾脏和肝脏肿大，但 Fli-1 的过表达改变了造血表型，显著增加了调节性造血基因 cKIT、SCA-1、CD41 和 CD71 的表达。相比之下，在一个 Fli-1 产生的红细胞白血病细胞系中过表达 Spi-1/PU.1，其中 fli-1 被激活，通过激活促进生长的蛋白质 MAPK、AKT、cMYC 和 JAK2 导致增殖增加。重要的是，这些祖细胞表达高水平的标志物，如与更成熟的红细胞细胞相关的 CD71 和 TER119。因此，Fli-1 的过表达通过将 CFU-E 逆转回 BFU-E 红细胞祖细胞活性来诱导去分化程序，而 Spi-1/PU.1 则促进从 BFU-E 到 CFU-E 的成熟。
